Using Epstein-Barr virus, we have established cell lines from peripheral blood of normal subjects and patients with extreme insulin resistance, i.e. lipoatrophic diabetes, leprechaunism, type A extreme insulin resistance, and Rabson-Mendenhall syndrome. Three classes of patients have been defined: 1) those with a decreased number of normal insulin receptors; 2) those with a normal number of qualitatively abnormal insulin receptors; and 3) those with a normal number of receptors without any detectable abnormality in insulin binding. In all of the patients, we are carrying out direct studies of insulin receptor structure in an effort to determine whether there is a structural abnormality. With cells from the patients with a decrease in receptor number, we are studying rates of receptor turnover to ascertain whether the abnormality results from a decrease in the rate of synthesis or an increase in the rate of receptor degradation. In cells from one of the patients with extreme insulin resistance, we have identified a decrease in the sensitivity of insulin binding to alterations in pH and temperature. In addition, there appear to be defects in receptor cooperativity and the regulation of receptor affinity.